Vagus nerve activation the anti-inflammatory treatment of the future?

Text: Felicia Lindberg, first published in Swedish in the magazine Medicinsk Vetenskap No 2/2020. 

A research mistake at the end of the 20th century led to the massive breakthrough – the unexpected discovery that the nervous system communicates with the immune system to regulate inflammatory processes in the body. A researcher at Kevin J. Tracey’s laboratory at the Feinstein Institute for Medical Research in New York was injecting an anti-inflammatory substance into the brains of mice, but accidentally used a 100,000 times lower dose than planned. To the researchers’ great surprise, the mistake had a massive anti-inflammatory effect, not only in the brain, but throughout the body, with lowered levels of the inflammatory substance TNF in the bloodstream of the mice.

“The minimal dose in the brain provided a stronger anti-inflammatory effect in the rest of the body than what occurs if you inject the substance directly into the tissue. This indicates that the brain has the capacity to tell the immune system to reduce inflammation,” says Peder Olofsson, physician and researcher at the Department of Medicine, Solna, at Karolinska Institutet. 

The researchers called their finding the “inflammatory reflex”. They managed to prove that the signals leave the brain via the vagus nerve, which is the longest cranial nerve in the brain, and then on to the spleen, where they tell the immune cells to reduce the production of TNF. The finding allowed research and technology development to take off.

A  pioneer within bioelectronic medicine

“Inflammation is the body’s defence against damage. It entails the activation of the immune system to heal the damage, but unfortunately the response can become chronic. Since many illnesses feature inflammation as a symptom, the idea was quickly conceived to attempt to activate the vagus nerve to reduce inflammation, and this can be done with electrical current,” says Peder Olofsson.

Peder Olofsson works closely with Kevin J. Tracey, a pioneer within bioelectronic medicine, and with developers of implantable nerve stimulators for clinical use. There are currently clinical studies looking at a small number of Swedish and European patients with Crohn’s disease, who are being treated using pacemaker-like implants. The implant consists of a small metal capsule with electrodes, which is inserted by a neurosurgeon on the side of the neck, which then sends electrical signals to the vagus nerve. The nerve, which runs from the brainstem, has more than 80,000 nerve fibres sending signals on to most of the internal organs, and it therefore has the potential to impact on a wide spectrum of physiological functions. Several clinical studies have been carried out on patients with inflammatory bowel diseases and rheumatoid arthritis, with encouraging results.

“During the treatment period, reductions in disease activity and inflammation markers were observed. Many of the patient said that their symptoms were largely relieved, but there are still no well-planned, definitive studies carried out on larger patient groups,” says Peder Olofsson.

 The researchers also have preliminary experimental results showing that the nerve activation not only reduces inflammation, but also appears to increase the activity of substances that stimulate the actual healing phase.

Side effects are generally mild

“One benefit of nerve stimulation is that you use the body’s own system. Hopefully, this reduces the risk of serious side effects,” says Peder Olofsson.

The method is not new. Since the 1990s, more than 100,000 epilepsy patients have had a similar implant inserted, which also stimulates the vagus nerve. Other than the risks of complications associated with any kind of surgery, the side effects are generally mild, including tickling in the throat and hoarseness. In individuals with epilepsy, nerve stimulation is active throughout much of the day.

“It is fascinating that in the treatment of inflammation, it can be enough to send a few minute-long electrical pulses per day to achieve a long-term effect."

In January 2020, Peder Olofsson started a new interdisciplinary collaboration with KTH within the research centre MedTechLabs, which brings together doctors, immunologists, engineers and mathematicians. The research focuses primarily on mapping out the signal transfer between nerves and immune cells at the molecular level, and on finding out which parts of the large vagus nerve that communicate with the immune system. Even if there are clinical data indicating that the method has potential, there is still some way to go before it can be implemented in practice. The nerve stimulation is relatively unspecific at present.

The goal is a self-regulating system

“We need to understand the details of how nerve reflexes regulate immune responses and inflammation in order to develop a more precise treatment that can be adapted to individual needs,” says Peder Olofsson.

Other than being able to control the immune system in specific organs, the real long-term goal is to develop a self-regulating system that continuously reads the level of inflammation and adjusts the electrical signals accordingly. In the long term, Peder Olofsson believes that bioelectronic medicine has great potential to supplement or replace drugs against inflammation, which are often expensive and associated with a number of side effects.

“Inflammatory diseases are a major problem in society, which cause a great deal of suffering all around the world. I hope that our work to map out how neural reflexes regulate inflammation can be applied within bioelectronic medicine to the benefit of patients within a relatively near future. If that happens, we will hopefully be able to treat excessive inflammation in a brand new way.